Isosapogenins



United 2,805,221 ISOSAPOGENINS Monroe E. Wall, Oreland, Pa.,

States of America as represented Agriculture No Drawing. Application May 27, 1955, Serial No. 511,813

20 Claims. (Cl. 260-23955) (Granted under Title 35, U. S. Code (1952), sec. 256) assignor to the United by the Secretary of All known steroidal sapogenins have the structure but differ in several ways. For example, additional hydroxyl groups may occur at positions 2 and 6; a carbonyl group may occur at position 12; a double bond may occur at positions -6; cis and trans isomerism may Patent same basic.

exist at the juncture of rings A and B; and geometrical isomerism may appear at position 22. All these variants are known and give rise to the known steroidal sapogenin species. 7

Treatment of steroidal sapogenins with acetic anhydride at about 200 C. for several hours opens the F-- ring and yields pseudosapogenin diacetates. These on hydrolysis yield pseudosapogenins. These reactions and I IS mllagenln obtained by the oxidation Patented Sept. 3, 1957 products are well known. The formula of pseudosarsa sapogenin, a typical example, is the following:

It is well known that treatment of pseudosapogenins with hot hydrochloric acid regenerates the F-ring and yields the original sapogenin. It is also known that treatment of the pseudosapogenins with C103 in acetic acid yields pregnenones useful in the production of sex hormones and other valuable steroid derivatives. While these reactions have been used to convert steroidal sapogenins into pregnenones, they are not satisfactory because of the low yields obtained and the difficulties encountered in purifying the products. The pseudosapogenins are rather unstable and are particularly difficult to isolate and purify. Consequently, the usual practice has been to make no attempt to isolate them but rather to oxidize them in the reaction mixture in which they were formed. This has resulted in pregnenones being formed in grossly contaminated and intractable reaction mixtures from which they could be recovered only by tedious procedures resulting in low yields.

An object of .this invention is to provide new and useful steroidal sapogenin derivatives; another object is to provide improved processes for converting steroidal sapogenins into new compounds that are readily isolated and purified and arealso readily converted into pregnenones and other valuable steroid derivatives. Still another object is to provide new and improved processes for the production of pregnenones.

According to the invention, any steroidal sapogenin may be converted to the isomeric 20-isosapogenin and the latter in turn may be oxidized to a pregnenone. The sapogenin is first converted to the corresponding pseudosapogenin by any known process. The pesudosapogenin or the reaction mixture containing it, is then treated with weak acid at substantially roof temperature whereby it is converted to the 20-isosapogenin. The ZO-isosapogenins are readily isolated and purified and are extremely useful as intermediates for the synthesis of sex hormones and other steroidal compounds. Thus, they are readily oxidized to pregnenones by the same procedures. used to oxidize pesudosapogenins to pregnenones. The most commonly used procedure is to treat with a solution of CrO; in acetic acid, though other variants are known. The pregnenones thus obtained are identical with those of the pesudosapog'enins but are obtained in higher yield and greater purity. The

a typical example of a sapogenin.

Acetic Anhydride II Smilagenin Dlzicetate ventional ClOa oxidation used to of water was added. A

K 011, Acetic Acid GrOs, KOH

IV 16-Pregnen-3,20dione By comparing Formulas I and .IH, above, it will be seen that the natural sapogenins and the isosapogenins of this invention are identical .except forthe configuration at C20. Examination of .molecular models of these -tW isomeric compounds shows thatthe E-ringof the iso compounds ishighly strained. It is believed that this strained configuration accounts for the greater reactivity of the iso compounds, particularly their susceptibility, to oxidation. The natural sapogeninsare inert to theconconvert pseudosapog- In contrast, the ZO-isosapogenins CrOz, yielding 20-keto-.16-pregenins to pregnenones. are readily cleaved by nenes.

The invention is more fully illustrated by the following examples.

EXAMPLE I Sarsasapogenin was converted toipseudosarsasapogenin by well known conventional procedures.

. wise, with stirring III 20-Isosmilagenin was filtered out, washed, methanol.

In the same manner pseudodiosgenin, pseudotigogenin were converted to the isosapogenins.

dried, and recrystallized from pseudohecogenin, corresponding 20- EXAMPLE III Five grams of ZO-isosarsasapogenin were dissolved in 150 ml. of1glacialacetic acid. To this was added dropa solution of 5 g. of CrOa in 80% acetic acid in water, the temperature being held at 15 .C. After the solutions had been mixed and held 1 hour atroom temperature, the product was extracted with -ether. The ether The residue was mixture was stirred Ten grams of pseudosarsasapogenin were dissolved in 300 ml. of absolute ethanol and then 3 ml. of concentrated hydrochloric acid were added. After being. allowed to stand at room temperature for 15 minutes a slight excess of sodium carbonate-and an equal volume precipitate of 20-isosarsasapogenin having the formula was thus formed and was filtered out, washed with-water and dried. The product (9.0 g.) wasrecrystallized from methanol.

EXAMPLE II Ten grams of pseudosmilagenin, obtained from smilagenin by conventional procedures, werejdissolved in 200 ml. of absolute ethano. To this solution 200 ml. of glacial acetic acid were added and the mixture was left overnight at room temperature. Dilution with water then precipitated 20-isosmilagenin having the formula I OH: 0

solution was thoroughly washed with the ether was removed by evaporation. dissolved in tert.-butanol containing 5 g. of KOH dissolved in 10 ml. of water. This 2-phase at room temperature for 3'hours. Dilution with water and extraction with ether then yielded of the theoretical amount of 16-pregnen-3,20- dione.

water, after which EXAMPLE IV 20-isodiosgenin,

H [I OH:

: IHO

1i zo-isotigogenin, and

20-isohecogenln.

The characteristics of these compounds are given in Table I below.

For converting pseudosapogenins to ZO-isosapogenins almost any acid may be used. If a strong acid is used it must be highly diluted. On the other hand, if a weak acid is used it may be used in almost any concentration. Heat is not essential and, when using any but a very weak acid, is detrimental.

The great advantage of making the 20-isosapogenins as intermediates in the conversion of sapogenins to pregnenones is that they are easily isolated and purified, and v the subsequent oxidation step gives higher yields and more readily purified products when starting with a pure 20-isosapogenin than when starting with a reaction mixture containing crude pseudosapogenin.

Table I OBSERVED PROPERTIES OF 20-ISOSAPOGENINB Infrared Absorption ZO-tSo-Compound [a]:

Peaks, cmr- M.P., C.

Yamogenin ..I

I claim: 1. Steroidal 20-isosapogenins selected from the group consisting of lected from the group consisting of and which comprises treating the corresponding pseudosapogenins with weak acid at substantially room temperature and recovering the thus formed 20-isosapogenins.

8. The process of claim 7 wherein the weak acid is an alcoholic solution of acetic acid.

9. A process as in claim 7 wherein the 20-isosapogenin recovered is 20-isosarsasapogenin.

10. A process as in claim 7 wherein the 20-isosapogenin recovered is ZO-isotigogenin.

1 1. A process as in claim 7 wherein the 20-isosapogenin recovered is ZO-isosmilagenin.

12. A process as in claim 7 wherein the 20-isosapogenin recovered is 20-isohecogenin.

13. A process as in claim 7 wherein the 20-isosapogenin recovered is 20-isodiosgenin.

14. A process for making steroidal ZO-isosapogenins selected from the group consisting of and which comprises converting the corresponding natural sapogenins to the corresponding pseudosapogenins; then, without isolating said pseudosapogenin from the raction mixture, treating them with weak acid at substantially room temperature, thus to convert them to the 20-isosapogenins; and finally, recovering the 20-isosapogenin from the reaction mixture.

15. A process as in claim 14 wherein the weak acid is an alcoholic solution of acetic acid.

16. A process as in claim 14 wherein the 20-isosapogenin recovered is 20-isosarsasapogenin.

17. A process as in claim 14 wherein the 20-isosapogenin recovered is 20-isotigogenin.

18. A process as in claim 14 wherein the 20-isosapogenin recovered is 20-isosmilagenin.

19. A process as in claim 14 wherein the 20-isosapogenin recovered is ZO-isohecogenin.

20. A process as in claim 14 wherein the ZO-isosapogenin recovered is ZO-isbdiosgenin.

Amer. Chem. Soc., vol. 76, May 20, 1954, p. 2849- 2852- Great Britain Nov. '22, 1943 

1. STEROIDAL 20-ISOAPOGENINS SELECTED FROM THE GROUP CONSISTING OF 